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The skin protects the body from various external environment stresses and plays an important role in maintaining its metabolic homeostasis. Lactoferrin (Lf) has been suggested to modulate skin homeostasis by activating human keratinocytes. In this study, we investigated the intracellular signal transduction pathways related to cell proliferation and migration using various Lf inhibitors on human keratinocytes. Three inhibitors, namely, protein tyrosine kinase inhibitor (Genistein), protein kinase C (PKC) inhibitor (calphostin C), and mitogen-activated protein kinase (MAPK) inhibitor (PD98059) suppressed keratinocyte proliferation and migration, both of which were stimulated by Lf treatment, to the basal level. Protein kinase A inhibitor (KT5720) and protein kinase G inhibitor (KT5823) did not suppress either keratinocyte proliferation or migration stimulated by Lf. Western blot analysis revealed that Lf enhanced the phosphorylation of PKC and extracellular signal-regulated kinases (ERK1Z2). In addition, matrix metalloproteinase 9 (MMP-9) activity, enhanced by Lf, was significantly inhibited by PD98059, but inhibition by calphostin C was less effective. These results suggested that various effects of Lf on human keratinocytes, including enhancing cell proliferation, promoting migration, and activating MMP-9, are strongly related to MAPK and PKC. The activation of MMP・9 is likely to be involved in extracellular matrix metabolism, which is enhanced by regulating the pathway of MAPK and ERK1/2 from Ras5 a low molecular weight G protein, via PKC. Together with previous studies, in which Lf has antibacterial and anti-inflammatory properties, Lf will be a potential candidate for clinical application to promote wound healing. [ABSTRACT FROM AUTHOR]